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Biomedical subjects

A Carlsson

Publications and source records attributed to A Carlsson.

At least 289 records · Page 16Linked to original sources
PubMed1983

Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat.

The two forms of monoamine oxidase (MAO) in rat intestine and brain homogenates were found to have different Km and Vmax values towards tyramine. The Km values for the A-form of the enzyme towards this substrate were around 120 microM in both cases, whereas the values for the B-form were about 240 microM. As a consequence, the ratio of activities (MAO-A: MAO-B) towards tyramine are dependent upon the substrate concentration. The MAO-A-selective inhibitors, toloxatone and cimoxatone, were found to be competitive inhibitors of the oxidation of tyramine by the A-form of this enzyme in the rat intestine, with Ki values of 3.4 microM and 3.7 nM respectively. The significance of these results in relation to the "cheese effect", a pressor response to tyramine after monoamine oxidase inhibition, are discussed.

Animals↗
PubMed1983

Urinary excretion of hippuric acid and o-cresol after laboratory exposure of humans to toluene.

The urinary excretion of hippuric acid and o-cresol was studied after respiratory exposure of human volunteers to approximately 80 ppm (306 mg/m3 +/- SD 13) of toluene for 2 h under different work loads (0, 50, 100, 150 W, respectively, during 30-min periods). The diet before and after exposure varied. An isotachophoresis method for the determination of hippuric acid is described. The correlation between the total urinary excretion, excretion rate and concentration of hippuric acid, and the respiratory uptake of toluene was poor or non-existing. The same was true for the excretion of o-cresol, which 4 h after exposure was concluded amounted to 0.03-0.26% of the toluene uptake. Thus, after a short-time exposure neither metabolite proved to be a reliable measure of individual toluene uptake at varying workloads or food intake in combination with low exposure levels.

Adult↗
PubMed1983

Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP.

The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.

Animals↗
PubMed1983

The effect of the enantiomers of 3-PPP on conditioned avoidance responding in the rat.

The effects of the enantiomers of 3-PPP on the maintenance of conditioned avoidance responding (CAR) were studied. The weak classical dopamine (DA) agonist (+)-3-PPP failed to interfere with CAR at any dose tested (0.8-13.6 mg/kg). Low doses of the drug produced sedation, while high doses produced behavioural stimulation. (-)-3-PPP, which acts as an antagonist on postsynaptic and as an agonist on autoreceptor DA sites, reduced avoidance with no effect on escape behaviour (6.8-13.6 mg/kg). However, this reduction of CAR occurred at doses much higher than those previously demonstrated to inhibit locomotor activity. This profile is discussed in relation to the behavioural effects of classical postsynaptic DA receptor antagonists.

Animals↗
PubMed1983

Dopamine receptor agonists: intrinsic activity vs. state of receptor.

Based on observations with the novel dopamine-receptor agonist 3-(3-hydroxyphenyl-)-N-n-propylpiperidine, 3-PPP, especially its levorotatory enantiomer, it is proposed that the intrinsic activity of a receptor agonist depends in part on the responsiveness of the receptor; this in turn is determined by the degree of previous agonist occupancy on the receptor. A change in occupancy will induce a slow conformational change, influencing the responsiveness. This may constitute an important aspect of receptor adaptation and may help to explain otherwise puzzling phenomena, e.g. that compounds such as (-)-3-PPP or transdihydrolisuride can act as strong dopamine-receptor agonists in some locations and as antagonists in others. The observations discussed in the present paper may be interpreted to indicate that the dopamine receptors in different locations are, in fact, derived from a homogenous receptor population, though in a varying state of adaptation. Thus it may prove worth-while to reconsider the various subclassifications of DA receptors proposed so far.

Animals↗
PubMed1983

Antidyskinetic action of 3-PPP, a selective dopaminergic autoreceptor agonist, in Cebus monkeys with persistent neuroleptic-induced dyskinesias.

Four Cebus apella monkeys with persistent dyskinetic movements induced by earlier long-term administration of haloperidol were subjected to a trial of the dyskinesia-modifying effects of a novel dopamine autoreceptor agonist 3-PPP (3[3-hydroxyphenyl]-N-n-propyl-piperidine). Three monkeys had choreic dyskinesia involving trunk and extremities whereas one had a buccolingual form including tongue protrusion with choreoathetotic twitching and twisting movements of the tongue. Two monkeys (1 choreic, 1 buccolingual) responded with dose-dependent symptom alleviation to 3-PPP, 1-4 mg/kg, with no signs of concomitant sedation or catalepsy. In the monkey with buccolingual dyskinesia all dyskinetic signs disappeared completely 2 hours after 2 mg/kg of 3-PPP. This animal participated in a separate study where the same doses of 3-PPP but also its enantiomers were given. The (-) enantiomer was a more potent antidyskinetic agent than the (+) enantiomer, the racemate falling between these two. Four mg/kg of the (+) enantiomer precipitated an amphetamine-like excitation and after 4 hours aggravation of dyskinesia was noted. These observations support the notion that the (+) enantiomer has both postsynaptic and presynaptic stimulatory effects, whereas the (-) enantiomer acts as a presynaptic dopamine receptor agonist.

Animals↗
PubMed1983

Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT).

In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.

Aged↗
PubMed1983

Substance P: structural requirements for the activation of brain catecholamine synthesis and locomotor activity in rats.

Intracerebroventricularly administered Arg-Pro-Lys-Pro-Gln-Gln-Phe-Gly-Leu-Met-NH2 (substance P, SP) enhanced the accumulation of DOPA after inhibition of the aromatic L-amino acid decarboxylase in the rat brain. SP also stimulated locomotor activity in a dose-dependent manner. A total of 31 structural analogues of SP were evaluated with respect to the action on brain monoamine synthesis as well as on locomotor activity. Catecholamine synthesis: SP1-10 was inactive which indicated that the [Met11]-NH2 terminal is essential for biological activity; [Leu10], [Phe7] and [Gln6] were also essential for activity; the minimum length requirement for activity was a hexapeptide amide structure. D-Amino acids in positions 8 or 9 increased activity. [D-Pro2]p-SP and [pGlu5, Gly7]-SP5-11 were active in the dopamine-rich areas, but inactive in the noradrenaline (norepinephrine)-predominant parts of the brain. The inactive [Ile7]-SP potentiated the effect of SP. Neither SP nor its analogues, with the exception of [Lys5,D-Leu8,D-Phe9]-SP5-11, increased the synthesis of 5-hydroxytryptophan (5-HTP). Locomotor activity: SP1-10 and [D-Phe9]-SP were as active as SP; [Ile7]-SP and [Ile7, Ile8]-SP were inactive and they did not antagonize the effect of SP. The results indicate that after chemical manipulation of the SP molecule it is possible to obtain great variation in activity and to dissociate to some extent the behavioural effects from those on brain catecholamine synthesis.

Animals↗
PubMed1983

Are "on-off" effects during chronic L-dopa treatment due to faulty feedback control of the nigrostriatal dopamine pathway?

The paper reviews evidence for and against the hypothesis that the "on-off" effects observed during chronic L-dopa therapy are due to faulty feedback control of the dopaminergic nigrostriatal pathway. Such failure may be brought about by preferential desensitization of the presynaptic dopaminergic autoreceptors or by a defect in the striatonigral feedback loop. To further analyze the mechanisms underlying "on-off" effects, the development of specific dopaminergic receptor agonists, suitable for clinical investigation, might prove useful. This may be true, for example, of selective dopaminergic autoreceptor agonists, such as 3-PPP, developed by the author's research group.

Animals↗
PubMed1983

Aseptic loosening of hip prostheses. A histologic and enzyme histochemical study.

Twenty-one total hip arthroplasties were revised because of aseptic loosening. The bone and soft tissue membrane bordering the cement in a total of 37 biopsies from the acetabulum and femur were studied histologically and by enzyme histochemistry. The soft tissue membrane was infiltrated with macrophages and had high acid phosphatase activity. Other inflammatory cells were rare or absent. Concomitant bone formation and bone resorption were usually present at the bone-soft tissue border. The bone generally consisted of viable, remodeled lamellar bone. The host bone seemed to have been resorbed by a soft tissue front moving outward from the cement. Reactive new bone formation began at the bone-soft tissue border and appeared to constrain the resorptive process. Articular wear seemed to play no part in initiating the loosening process. The role of bone cement in this respect is obscure, because there were no obvious local signs of cytotoxicity. These observations support the theory of mechanical instability as the primary cause of the tissue reaction.

Acetabulum↗
PubMed1983

The search for selective dopaminergic autoreceptor agonists.

In the course of a search for new selective dopamine (DA) autoreceptor agonists the DA analogue 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP, was resolved into its dextro-(+) and levo-(-) rotatory enantiomers. The compounds were pharmacologically evaluated by means of behavioural and biochemical methods. Surprisingly, both (+)-and (-)-3-PPP show clearcut, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA receptor agonist with activity on autoreceptors as well as postsynaptic receptors, whereas (-)-3-PPP similarly activates DA autoreceptors but, in contrast, concomitantly acts as an antagonist on postsynaptic DA receptors. Moreover, the behavioural/biochemical profile seems to indicate a preferential limbic action for the (-)-enantiomer. Such an action could be explained on the basis of different feedback arrangements in the nigrostriatal and mesolimbic DA systems and it is suggested that compounds such as (-)-3-PPP may find future clinical application as "second-generation" antipsychotic agents, lacking in the debilitating motor side effects produced by drugs in current therapeutic use.

Animals↗
PubMed1982

Adrenergic influence on rat plasma concentrations of tyrosine and tryptophan.

Isoprenaline given to rats in doses between 0.08 and 10 mg/kg intraperitoneally caused a significant decrease in plasma concentrations of tyrosine and tryptophan. Low doses of adrenaline (0.04 - 0.16 mg/kg, intraperitoneally) caused a 30 per cent decrease in plasma concentrations of tyrosine, while high doses (0.63 - 1.25 mg/kg, intraperitoneally) caused an increase in plasma tyrosine to nearly 200 per cent of the controls. High doses of noradrenaline (0.63 - 2.5 mg/kg, intraperitoneally) caused a similar increase in plasma tyrosine concentration. The decrease in plasma amino acids caused by these catecholamines is inhibited by propranolol, suggesting that this effect is mediated via adrenergic beta-receptors, while the increasing effect is inhibited by phenoxybenzamine, which suggests that this effect is caused by an alpha-adrenergic mechanism.

Animals↗
PubMed1982

Isoprenaline increases brain concentrations of administered L-dopa and L-tryptophan in the rat.

A small dose of isoprenaline or saline was administered intraperitoneally to rats 20 min before the administration of one of the amino acids L-dopa or L-tryptophan. Isoprenaline caused a marked increase in the brain concentration of the administered amino acid. Isoprenaline has previously been shown to cause a decrease in at least some of those plasma amino acids which compete with L-dopa and tryptophan for carrier-mediated transport into the brain. The effect of isoprenaline on the concentrations of dopa and tryptophan in the brain is suggested to be at least partly caused by a change in the relationship between endogenous and administered amino acids. It is also possible that a direct effect of isoprenaline on the blood-brain barrier transport system contributes to the effect. The reported finding might be of clinical interest in view of the therapeutic importance of aromatic amino acids with a central site of action.

Animals↗
PubMed1982

Monoamine concentrations in the human brain. A comparison between two methods of tissue handling.

The brains of five neurologically healthy humans were analyzed for their content of various monoamines and metabolites using two different dissection methods. The left hemisphere was frozen immediately and subsequently dissected in the frozen state. The right hemisphere was dissected fresh in the autopsy room whereupon the brain parts were put in a freezer. Few significant differences were noted with respect to the monoamine content, indicating that the methods could be considered to be equivalent for the purpose of monoamine analysis.

Aged↗
PubMed1982

A behavioural study of the changes in the central nervous system of mice after subchronic treatment with the selective dopamine autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine).

In naive mice the selective dopamine (DA) autoreceptor agonist 3-PPP (dl-3-[3-hydroxyphenyl]-N-n-propylpiperidine) produced a dose-dependent depression of locomotor activity. The duration of action of the depression was short, with no significant depression being noted one or more hours after a dose of 23.47 mg/kg (expressed as the base). Mice, administered the drug twice daily (23.47 mg/kg, in the morning and the evening, i.p.) for 5 days, were, 15 to 25 hours after the last dose, marginally less sensitive to the locomotor depressant effects of a challenge with the same drug. There was no change in the sensitivity of postsynaptic DA and alpha-adrenergic receptors, as assessed by the locomotor stimulant effects of apomorphine and apomorphine plus clonidine, respectively, in reserpine and alpha-methyltyrosine pretreated animals. However, 3-PPP-pretreated mice were most sensitive to the activating effects of d-amphetamine, and this increased sensitivity was blocked by pretreatment with reserpine. In naive mice, a low, DA autoreceptor selective dose of haloperidol (25 micrograms/kg) potentiated the locomotor stimulant effects of d-amphetamine. One explanation for the data obtained is that subchronic pretreatment with 3-PPP produced DA autoreceptor subsensitivity with no concomitant change in postsynaptic DA or alpha-adrenergic receptor sensitivity. The increased sensitivity to d-amphetamine in the 3-PPP pretreated mice may be due to a reduction in the feedback control exerted by the DA released by the d-amphetamine due to the DA autoreceptors having become subsensitive.

Animals↗